A Novel Formulation of VIP in Sterically Stabilized Micelles Amplifies Vasodilation In Vivo

Purpose. To determine whether human vasoactive intestinal peptide (VlP)-poly(ethylene glycol) (PEG)-grafted distearoyl-phosphatidyleth-anolamine (DSPE) micelles elicit potent and stable vasodilation in vivo. Methods. PEG-DSPE micelles were prepared by co-precipitation. VIP was loaded into micelles by incubation at room temperature. Vasoactivity of VIP in SSM was determined by monitoring changes in diameter of resistance arterioles in the in situ hamster cheek pouch using intravital microscopy. Results. VIP easily undergoes self-assembly into small PEG-DSPE micelles (mean [±SEM] size, 18 ± 1 nm) in a time-dependent fashion. This generates a potent vasoactive matrix at nanomole concentrations of VIP as manifested by ~3-fold potentiation and prolongation of vasodilation relative to that evoked by aqueous VIP alone (p < 0.05). This response is specific and mediated by the L-arginine/nitric oxide (NO) biosynthetic pathway. Micellar VIP dispersion remains vasoactive for at least 14 days after preparation and storage at 4°C. Conclusions. A novel, self-associated, small and stable PEG-DSPE micellar formulation of VIP amplifies vasodilation in the in situ peripheral microcirculation in a specific fashion by elaborating NO. An optimized formulation could be considered for certain cardiovascular disorders associated with L-arginine/NO biosynthetic pathway dysfunction.     

Laparoscopic Repair of Giant Paraesophageal Hernia Results in Long-Term Patient Satisfaction and a Durable Repair

Background  Laparoscopic repair of giant paraesophageal hernia (LRGPEH) is routinely performed in many centers, but high recurrence rates have led to concerns regarding this approach. We evaluate long-term recurrence rates, symptom improvement and correlation with radiographic recurrence, and risk factors for recurrence in our cohort of patients. Methods  A cohort of consecutive patients with a minimum of 5 years potential follow-up (1997–2003) post-LRGPEH was identified from a prospective database. Clinical outcomes, barium esophagram (BE), and quality-of-life (QoL) measures were obtained. Results  Laparoscopic repair was successful in 185/187 patients. Routine clinical follow-up (median 77 months) was available for all patients. Detailed questionnaires and BE were obtained in 65% and 82% of patients. Gastroesophageal Reflux Disease Health-Related QoL (GERD-HRQoL) scores were excellent to good in 86.7%. BE (median 51 months) demonstrated radiographic hernia recurrence in 15% of patients, but without consistent symptom association. There was a trend toward increased risk of radiographic recurrence in patients with a history of pulmonary disease (p = 0.08). Seven reoperations (4.4%) were performed for symptomatic recurrence (median 44 months postoperative). Conclusions  LRGPEH performed in our minimally invasive center of excellence resulted in a durable repair with a high degree of satisfaction and preservation of GERD-related QoL at a median follow-up of over 6 years. This work was presented at the Plenary Presentation of the 49th Annual Meeting of the Society for Surgery of the Alimentary Tract on May 21, 2008, at the San Diego Convention Center in San Diego, California.     

A comparative evaluation of phenotypic and molecular methods for the detection of oxacillin resistance in coagulase-negative staphylococci

Detection of oxacillin resistance in coagulase-negative staphylococci (C-NS) by phenotypic methods is often difficult. The present study compared the National Committee for Clinical Laboratory Standards (NCCLS) revised guidelines of phenotypic methods with a mecA-based polymerase chain reaction (PCR) for C-NS. Ninety clinical C-NS isolates were tested for oxacillin resistance by disk diffusion (1-µg disk), minimum inhibitory concentration (MIC) breakpoint (0.5µg/ml) after 24h, and mecA-based PCR. The sensitivity and specificity of disk diffusion was 80% and 93%, and the sensitivity and specificity of the MIC breakpoint after 24h was 84% and 91%, respectively, against PCR as gold standard. Eleven strains (7 mecA-positive and 4 mecA-negative) showed discordant results between MIC breakpoint after 24h and PCR. Six of the 7 mecA-positive and all 4 mecA-negative discordant strains had inducible oxacillin resistance and -lactamase hyperproduction, respectively. The present study concludes that inducible oxacillin resistance and -lactamase hyperproduction are the major causes of discordant results between phenotypic methods and mecA-based PCR, and need special attention.     

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

The colony‐stimulating factor 1 (CSF1) regulates the differentiation and function of tissue macrophages and determines the outcome of the immune response. The molecular mechanisms behind CSF1‐mediated macrophage development remain to be elucidated. Here we demonstrate that neutrophil‐derived CSF1 controls macrophage polarization and proliferation, which is necessary for the induction of tolerance. Inhibiting neutrophil production of CSF1 or preventing macrophage proliferation, using targeted nanoparticles loaded with the cell cycle inhibitor simvastatin, abrogates the induction of tolerance. These results provide new mechanistic insights into the developmental requirements of tolerogenic macrophages and identify CSF1 producing neutrophils as critical regulators of the immunological response.     

Successful management of a consecutive cervical pregnancy by sonographically guided transvaginal local injection: case report and review of the literature.

OBJECTIVE: The purpose of this study was to describe the successful management of a recurrent cervical pregnancy with local injection and to review similarly treated cases to determine adverse outcomes. METHODS: A case of a recurrent cervical pregnancy treated with transvaginal local injection was reported. A MEDLINE English language search identified 90 cases of cervical pregnancy treated with local therapy. This literature was analyzed with regard to the various demographic and outcome variables described. RESULTS: Successful use of the transvaginal local approach is described. A review of cases identified a mean maternal age of 33.6 years with a mean gestational age at diagnosis of 7.5 weeks. Bleeding was the most common presenting sign (79%). The mean beta-human chorionic gonadotropin level at the time of diagnosis was 27,798 IU with an average time to resolution of 7.5 weeks. The most common risk factor was a history of curettage (69%), followed by previous cesarean delivery (35%). An additional dose of methotrexate was needed in 6% of cases. Bleeding requiring alternate procedures was present in 5% of cases. There were no complications in 81% of cases. The need for transfusion and development of infection were seen in 3% of cases each. There was 1 case (1.1%) requiring hysterectomy, and no maternal deaths were reported. CONCLUSIONS: Conservative management of cervical pregnancy using local injection has been reported to have a low complication rate and a high efficacy for cure.     

Differences in the Lipoprotein Distribution of Free and Liposome-Associated All-trans-Retinoic Acid in Human, Dog, and Rat Plasma Are Due to Variations in Lipoprotein Lipid and Protein Content

The objective of the proposed study was to determine the distribution in plasma lipoprotein of free all-trans retinoic acid (ATRA) and liposomal ATRA (Atragen; composed of dimyristoyl phosphatidylcholine and soybean oil) following incubation in human, rat, and dog plasma. When ATRA and Atragen at concentrations of 1, 5, 10, and 25 μg/ml were incubated in human and rat plasma for 5, 60, and 180 min, the majority of the tretinoin was recovered in the lipoprotein-deficient plasma fraction. However, when ATRA and Atragen were incubated in dog plasma, the majority of the tretinoin (>40%) was recovered in the high-density lipoprotein (HDL) fraction. No differences in the plasma distribution between ATRA and Atragen were found. These data suggest that a significant percentage of tretinoin associates with plasma lipoproteins (primarily the HDL fraction) upon incubation in human, dog, and rat plasma. Differences between the lipoprotein lipid and protein profiles in human plasma and in dog and rat plasma influenced the plasma distribution of ATRA and Atragen. Differences in lipoprotein distribution between ATRA and Atragen were not observed, suggesting that the drug’s distribution in plasma is not influenced by its incorporation into these liposomes.     

DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine

The development of agents that affect two or more relevant targets has drawn considerable attention in treatment of AD. Diallyl disulfide (DADS), an active principle of garlic, has been reported to prevent APP processing by amyloidogenic pathway. Recently, we have reported a new series of DADS derivatives and our findings revealed that compound 7k and 7l could provide good templates for developing new multifunctional agents for AD treatment. Thus, the present study was constructed to investigate the neuroprotective effect of DADS analogues (7k and 7l) against Aβ-induced neurotoxicity in SH-SY5Y human neuroblastoma cells and in ameliorating the cognition deficit induced by scopolamine in rat model. The results indicated that compound 7k and 7l significantly inhibited Aβ_1–42-induced neuronal cell death by inhibiting ROS generation. Moreover, they prevented apoptosis, in response to ROS, by restoring normal Bax/Bcl-2 ratio. Furthermore, it was observed that scopolamine-induced memory impairment was coupled by alterations in neurotransmitters, acetylcholinesterase activity and oxidative stress markers. Histological analysis revealed severe damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Administration of compounds 7k and 7l at 5 mg/kg significantly reversed scopolamine-induced behavioural, biochemical, neurochemical and histological changes in a manner comparable to standard donepezil. Together the present findings and previous studies indicate that compounds 7k and 7l have neuroprotective and cognition-enhancing effects, which makes them a promising multi-target candidate for addressing the complex nature of AD.